Muscular dystrophy (MD) or a form thereof, refers to a group of genetic, hereditary muscle diseases that cause progressive muscle weakness (Harrison's Principles of Internal Medicine, 16th Edition, New York: McGraw-Hill, 2005, 17th edition). Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, the death of muscle cells and tissue (Emery A E, Lancet, 2002, 359(9307): 687-695), resulting in the progressive weakness and degeneration of skeletal muscles leading to loss of ambulation, difficulties in breathing and eating, and premature death. Although there are more than 100 diseases in total with similarities to muscular dystrophy, there are nine diseases, including Duchenne Muscular Dystrophy (DMD) (also known as Pseudohypertrophic), Becker Muscular Dystrophy (BMD), Emery-Dreifuss Muscular Dystrophy (EDMD), Limb-Girdle Muscular Dystrophy (LGMD), Facioscapulohumeral Muscular Dystrophy (FSH or FSHD) (also known as Landouzy-Dejerine), Myotonic Dystrophy (MMD) (also known as Steinert Disease), Oculopharyngeal Muscular Dystrophy (OPMD), Distal Muscular Dystrophy (DD) (also known as Miyoshi) and Congenital Muscular Dystrophy (CMD) that are always classified as a muscular dystrophy (May 2006 report to Congress on Implementation of the MD CARE Act, as submitted by Department of Health and Human Service's National Institutes of Health).
Most types of MD are multi-system disorders with manifestations in body systems including the heart, gastrointestinal and nervous systems, endocrine glands, skin, eyes and other organs (May 2006 report to Congress on Implementation of the MD CARE Act, as submitted by Department of Health and Human Service's National Institutes of Health). Multi-system disorders related to MD include motor neuron diseases such as, but not limited to, Amyotrophic Lateral Sclerosis (ALS) (also known as Lou Gehrig's Disease), Spinal Muscular Atrophy Type 1 (SMA1, also known as Werdnig-Hoffmann Disease), Spinal Muscular Atrophy Type 2 (SMA2), Spinal Muscular Atrophy Type 3 (SMA3, also known as Kugelberg-Welander Disease) and Spinal Bulbar Muscular Atrophy (SBMA) (also known as Kennedy Disease and X-Linked SBMA); metabolic muscle diseases such as, but not limited to, Phosphorylase Deficiency (MPD or PYGM) (also known as McArdle Disease), Acid Maltase Deficiency (AMD) (also known as Pompe Disease), Phosphofructokinase Deficiency (also known as Tarui Disease), Debrancher Enzyme Deficiency (DBD) (also known as Cori or Forbes Disease), Mitochondrial Myopathy (MITO), Carnitine Deficiency (CD), Carnitine Palmityl Transferase Deficiency (CPT), Phosphoglycerate Kinase Deficiency, Phosphoglycerate Mutase Deficiency, Lactate Dehydrogenase Deficiency and Myoadenylate Deaminase Deficiency; peripheral nerve diseases such as, but not limited to, Charcot-Marie-Tooth Disease (CMT) (also known as Hereditary Motor and Sensory Neuropathy (HMSN) or Peroneal Muscular Atrophy (PMA)), Friedreich's Ataxia (FA) and Dejerine-Sottas Disease (DS) (chromosome 19 recessive form can be called CMT4F); inflammatory myopathies such as, but not limited to, Dermatomyositis (DM), Polymyositis (PM) and Inclusion Body Myositis (IBM); diseases of the neuromuscular junction such as, but not limited to, Myasthenia Gravis (MG), Lambert-Eaton Syndrome (LES) and Congenital Myasthenic Syndrome (CMS); myopathies due to endocrine abnormalities such as, but not limited to, Hyperthyroid Myopathy (HYPTM) and Hypothyroid Myopathy (HYPOTM); and other myopathies such as, but not limited to, Myotonia Congenita (MC) (two forms: Thomsen and Becker Disease), Paramyotonia Congenita (PC), Central Core Disease (CCD), Nemaline Myopathy (NM), Myotubular Myopathy/Centronuclear Myopathy (MTM or CNM) and Periodic Paralysis (PP) (two forms: Hypokalemic and Hyperkalemic) (see, Muscular Dystrophy Association website: mda.org/disease).
Genetically, MD or a form thereof, can be inherited in a dominant or recessive manner, or in some cases, caused by sporadic de novo mutations. Inherited forms of MD or a form thereof, involve genetic mutations of genes encoding, e.g., dystrophin, emerin, myotilin, lamin A/C, caveolin 3, calpain 3, dysferlin, dysferlin, γ-sarcoglycan, α-sarcoglycan, β-sarcoglycan, δ-sarcoglycan, telethonin, fukutin, fukutin-related protein, titin, E3-ubiquitin ligase, selenoprotein N1, collagen VI subunit α2, α2-Laminin, O-Mannosyltransferase, and O-MNAGAT.
Duchenne Muscular Dystrophy (“DMD”), a form of MD, is an X-chromosome linked, recessive disease caused by mutations of the dystrophin gene at the Xp21 locus. Dystrophin is composed of four distinct structural domains: (i) an N-terminal “actin binding” domain; (ii) a middle “rod” domain consisting of spectrin-like repeats; (iii) a cysteine-rich domain; and (iv) a carboxyl-terminal domain. Various dystrophin full-length isoforms have been detected. The predominant dystrophin isoform found in skeletal muscles is a cytoskeletal protein of approximately 427 kDa that is expressed at the sarcolemma (the plasma membrane of the muscle cell), where it is part of the dystrophin-associated protein complex (“DAPC”).
While the exact function of dystrophin has not been elucidated, it is believed that it serves to link the intracellular microfilament network of actin to the extracellular matrix. In other words, dystrophin anchors the sarcolemma to the actin cytoskeleton in the sarcoplasm (the cytoplasm of the muscle cell) and plays an important role during muscle contraction and muscle stretch. Dystrophin is thought to be an elastic and flexible protein (due to the triple helix repeats in its rod domain) and probably protects the muscle cell from the stresses caused by the force created during muscle contraction. A marked reduction in the levels of DAPCs at the sarcolemma are observed in dystrophin-deficient skeletal muscle from DMD patients and animal models. Thus, the absence of this physical link/interaction between the interior and exterior of the muscle cell renders the sarcolemma fragile, making muscle fibers susceptible to degeneration during repeated cycles of muscle contraction and relaxation.
Typically, DMD patients are clinically normal at birth except for elevated serum levels of the muscle isoform of creatine kinase as a consequence of muscle fiber degeneration. Physical symptoms of DMD progressively appear throughout childhood with subsequent onset of pseudohypertrophy of the calf muscles and proximal limb muscle weakness. Progressive muscle wasting continues throughout life. Becker MD (“BMD”) is a milder form of inherited MD that is also caused by dystrophin mutations. DMD results from an absence of dystrophin or expression of a non-functional protein, whereas BMD has been associated with reduction of wild-type dystrophin or expression of a partially functional protein. Although many genetic causes of the various forms of MD have been identified and characterized, other forms of MD are caused by mutation of other genes that have not yet been defined.
MD, or a form thereof, is usually diagnosed based on tests, such as a muscle biopsy, genetic testing, electromyography or nerve conduction tests (which use electrodes to test muscle and/or nerve function) and blood enzyme tests (which may reveal muscle damage). These tests are usually accompanied with physical exams and evaluation of the patient's family medical history. Management of symptoms in MD patients include exercise, physical therapy, and surgery. In DMD, corticosteriods may slow muscle destruction to an extent, but careful management of steroid therapy is required due to the systemic side effects associated with it. One of the few entities currently being developed for the treatment for muscular dystrophy is stamulumab (MYO-029), an experimental GDF8 (growth and differentiation factor 8) inhibiting recombinant human antibody. Otherwise, there is no other drug known to alter the course of the disease.
As a result of the progress made in understanding the genetic basis and pathophysiology of MD, several strategies for treatment have been explored, but none have yet demonstrated success. For example, gene replacement (e.g., of dystrophin in the case of DMD) and cell replacement (using normal myoblasts or stem cells) strategies are being tested in animals. However, these approaches to treat DMD will require many more years of investigation before they can be applied to humans. Pharmacological approaches under exploration include searching for drugs that increase dystrophin levels (or dystrophin-related protein levels, e.g., utrophin) to compensate for its loss. One such strategy involved the use of gentamicin (an aminoglycoside antibiotic that causes stop codon read-through) to treat DMD caused by a mutation that introduces a premature stop codon within the coding sequence (open reading frame) of dystrophin. Although this strategy was reported to increase dystrophin levels by 10-20% in a mouse model, these results could not be replicated and human clinical trials have shown no increase in expression of dystrophin. Thus, despite the progress made in understanding the genetic basis and pathophysiology of MD or a form thereof, there remains a need for therapies that alter the course of the disease.